Process for the manufacture of polyene aldehydes



- groups of which may carry alkyl PROCESS FOR THE MANUFACTURE OF POLYENEALDEHYDES Otto Isler, Marc Montavon, and Rudolf Riiegg, Basel, and PaulZeller, Neuallschwil, near Basel, Switzerland, assignors to Hofi-mann-LaRoche Inc., Nutley, N. J., a corporation of New Jersey No Drawing.Application July 13, 1956 Serial No. 597,567

Claims priority, application Switzerland July 22, 1955 4 Claims. (Cl.260-598) This invention relates to a new process for the preparation ofpolyene aldehydes. This process comprises condensing in an inert solventa 2,6,6-trimethyl-cyclohexyliden-ethyliden-triarylphosphine compound,the aryl or alkoxy radicals, with a compound selected from the groupconsisting of acetals of Z-oxo-propanal-(l), of 4oXo-pentene-(2)al-(l)and of 2-methyl-6-oxo-heptadiene-(2,4)-al-( 1), heating the reactionmixture and hydrolyzing the acetal formed in the presence of acid.

In the first stage of the comprehensive process an acetal of2-oxo-propanal-(1) or 4-oxo-pentene-(2)-al-( 1) or 2-methyl-6-oxo-heptadiene-(2,4)-al-(l) is condensed with the 2,6,6trimethylcyclohexyliden-ethyliden-triarylphosphine compound; the nextstage comprises splitting ofl? triarylphosphine oxide, thus producing apolyene aldehyde acetal. Both steps, the condensation and the separationof triarylphosphine oxide, are advantageously carried out in the samevessel without isolation of the intermediate. The condensation step ispreferably effected in the presence of an inert solvent, such as forinstance ether, petroleum ether, benzene, dioxan, tetrahydrofuran,methylene chloride, using equivalent quantities of the startingmaterials. Thus, the compounds may be mixed in a vessel While stirringat room temperature or at elevated temperature, whereby the air issuitably replaced by an inert gas, such as nitrogen. The condensation ispreferably carried out by using lower aliphatic acetals of2-oxo-propanal-(1) or 4-oxo-pentene(2)-al-( 1) or 2-methyl-fi-oxo-heptadiene-(2,4)-al-(l), such as the dimethyl, diethyl ordibutyl acetals, or cyclic acetals, such as ethylene or propyleneacetals; the preferred 2,6,6-trimethylcyclohexyliden -ethylidentriarylphosphine compound is 2,6,6 trimethylcyclohexyliden ethylidentriphenylphosphine. Upon addition of a solution of the acetal to asolution of 2,6,6-trimethylcyclohexylidenethyliden-triarylphosphine theexothermic condensation immediately takes place. Depending on thesolvent and the starting compound used, the condensation products remainin solution or precipitate; in the latter case the solution is mostlydecolorated or at least lightened. In a preferred embodiment of thecondensation step, the acetal compound is dissolved in benzene and thebenzene solution is added to a suspension or a solution of 2,6,6-trimethylcyclohexyliden ethyliden triarylphosphine, whereby thecondensation product precipitates. Upon standing, the condensationproducts are slowly decomposing into the corresponding polyene aldehydeacetals and triarylphosphine oxide; upon heating, this decompositiontakes place quickly. For instance, the decomposition may easily beperformed by heating the reaction mixture for several hours to 35-80.After completion of the reaction, the polyene aldehyde acetals areseparated from the triarylphosphine oxide formed, for instance byshaking the organic layer with Water and may be isolated byconcentrating the dried solution.

The acetals may be aldehydes.

purified and separated from adherent organic phosphorous compounds byrepartition between solvents or by chromatography or by distillation.There are thus obtained practically pure polyene aldehyde acetals ascolorless or weakly yellow colored oils, showing characteristicabsorption maxima in the ultraviolet spectrum. When using acetals ofZ-oxo-propanal-(l), there are obtained4-[2,6,6-trimethylcyclohexyliden]-2-methy1-butene (2)- al-(1)-acetalshaving an U. V. absorption maximum at 248 nm in petroleum ether. Whenusing acetals of 4-oxopentene-(2)-al-(l), there are obtained6-[2,6,6-trimethylcyclohexyliden] -4 -methyl hexadiene (2,4) al (1)-acetais showing an U. V. absorption maximum at 286 m in petroleum ether.When using acetals of Z-methyl- 6-oxo-heptadiene-(2,4)-al-(1) there areobtained 8- [2,6,6 trimethylcyclohexyliden] 2,6 dimethyloctatriene-(2,4,6)-al-(l)-acetals with U. V. absorption maxima at 307,321 and 338 my in petroleum ether.

In the final stage of the comprehensive process, the polyene aldehydeacetals obtained are hydrolyzed in acidic medium, thus producing thecorresponding polyene The hydrolysis is performed in a manner known perse, e. g. by stirring the polyene aldehyde acetals in the presence ofwater in a Water-miscible solvent with a mineral acid, such as sulfuricacid, or with an organic acid, such as acetic acid or p-toluene sulfonicacid at room temperature or elevated temperature. In an advantageousembodiment of the hydrolysis stage, the polyene aldehyde acetals areheated with acetic acid for a short time to or they are stirred inalcoholic solution with dilute sulfuric acid for several hours. In orderto avoid loss of substance due to decomposition, it is advisable toperform the reaction in the presence of an inert atmosphere and to addan antioxidant.

The polyene aldehydes obtained by the process of the present invention,i. e. 4-[2,6,6-trimethylcyclohexyliden]- 2 methyl butene (2) al-( 1),6-[2,6,6-trimethylcyclohexyliden] -4-methyl-hexadiene-(2,4) -a1-( 1 and8- [2,6,6- trimethylcyclohexyliden]-2,6 dimethyl octatriene (2,-4,6)-al-(1) show characteristic absorption maxima in the ultravioletspectrum. Due to the cis-trans-isomerism at the double bonds, thereexist various steric forms of these aldehydes.

The products of the comprehensive process are valuable intermediates inthe synthesis of vitamin A and ,B-carotene. Thus the compound4-[2,6,6-trimethylcyclohexyliden]-2-methyl-butene-(2)-al-(l) can beconverted into vitamin A, e. g. by condensing it with 1-hydroxy-3-methyl-penten-(Z)-yne-(4), subjecting the condensation product obtainedin any desired sequence to acetylation and partial hydrogenation at thetriple bond and treating the ester formed with dehydrating agents.6-[2,6,6- trimethylcyclohexyliden] -4-methyl-hexadiene- (2,4) -al-( 1)can be converted into 8-[2,6,6-trimethylcyclohexyliden]-2,6-dimethyl-octatriene-(2,4,6)-a1-(1) by acetalisation, condensation ofthe acetal formed with a propenyl ether and heating the condensationproduct with acid. When condensing 8 [2,6,6 trimethylcyclohexyliden] 2,6dimethyl-octatriene-(2,4,6)-al-( 1) with acetylene, subsequentlysplitting ofi 2 mols of water with rearrangement, partiallyhydrogenating the triple bond and isomerising the compound producedthere is obtained p-carotene.

EXAMPLE 1 (a) 4- [2,6,6-zrimethylcyclohexyliden] -2-mathyl-buten- (2)-al-(] )-ethylene acetal To a deep red suspension of2,6,6-trimethylcyclohexyl-- dried diethyl ether-was gradually added,while stirring in a nitrogen atmosphere, a solution of 2.4 g. of2-oxo-propanal-(l)-ethylene acetal (B. P 102; n =1.4845) in 10 mil. ofdry benzene. There was formed a voluminous precipitate while thesolution decolorated. After further stirring for 20 minutes, 120 ml. ofdry benzene were added, the ether was driven off, until the reactionmixture reached a temperature of 60. The mixture was then stirred in ahydrogen atmosphere for further six hours at 60. After cooling down, theprecipitate was separated by filtration, the filtrate was washed withwater, dried over sodium sulfate and the solvent was evaporated. Inorder to remove adherent phosphorus containing impurities the residuewas dissolved in a little petroleum ether, passed through a short columnof aluminium oxide (according to Brockmann, degree of activity 11) andthe petroleum ether was driven off. There was thus obtained 3.5 g. oft-[2,6,6- trimethylcyclohexylidenl 2 methyl buten (2) al (l)-ethyleneacetal. After distillation in vacuo there was obtained a nearlycolorless product. B. P 100"; U. V. absorption maximum at 248 m inpetroleum ether.

(b) 4- [2,6 ,G-trimethylcyclohexylidenl -2-methylbutene-(2)-al-(1) To 6g. of4-l2,6,6-trimethylcyclohexyliden]-2-methylbuten-(2)-al-(l)-ethyleneacetal dissolved in 80 ml. of ethanol were added 14 ml. of 3 n sulfuricacid and the mixture was refluxed for 30 minutes. The mixture was thendiluted with 200 ml. of ice water, extracted with 100 ml. of petroleumether, the petroleum ether solution was washed with water and sodiumbicarbonate solution, then dried with sodium sulfate, and the solventwas driven off. There was obtained 4-[2,6,6-trimethylcyclohexyliden]-2-methyl-butene-(2)-al-(1), which can be purified by distillation. B. R85"; U. V. absorption maximum at 288 my. in petroleum ether. Thephenylsemicarbazone recrystallized from a mixture of methylene chlorideand methanol formed colorless prisms of M. P. 158459"; U. V. absorptionmaximum at 314 m in petroleum ether.

The starting materials required in the process described in the aboveexample can for instance be prepared as follows:

2-0x0-pr0panal-(1)-ethylene acetal.-1 mol of methylglyoxal and 1.2 molof ethylene glycol were heated for several hours in 250 ml. of benzenein the presence of a catalytic quantity of p-toluene sulfonic acid,while continuously distilling oif the water formed. The reaction mixturewas then cooled down, poured on cold sodium bicarbonate solution, thebenzene solution was separated, dried over sodium sulfate and thesolvent was driven off. By distillation of the-residue, there wasobtained the ethylene acetal of methylglyoxal (B. 1 102; 11 1.4845).

Z-oxo-propanal-(I )-dialkyl-acetals.-The dialkyl acetals ofmethylglyoxal, such as the diethyl acetal, can be prepared e. g.according to the procedure described in Beilstein, I. Erg'anzungswerk[1928], page 395.

4-0x0-pentene-(2)-al-(1 -acetaIs.--Propiolaldehyde acetal was condensedwith acetaldehyde, the triple bond of the compound formed was partiallyhydrogenated and the hydroxy group was oxidized with manganese dioxide.

Z-methyl-6-0x0-heptadiene-(2,4)-al-(1 )acetaIs.-Methylrnalonicdialdehyde was transformed into the enol ether by heating the same withan alcohol in an inert solvent in the presence of an acidic condensationagent and continuously distilling off the water formed. The enol etherwas condensed with lithium acetylide and hydrolized with acid; theZ-methyl-penten-(2)-yne-(4)-al-(1) was acctalized, the acetal formed wascondensed by a metal organic reaction with acetaldehyde, the triple bondof the 2-methyl-6-hydroxypenten- 2) -in- (4) -al-( 1) -acetal obtainedwas partially hydrogenated. The hydroxy group wasthen oxidized withmanganese dioxide.

2,6,6-trimethylcyclohexyliden-ethyZen-t r i a r y lp h 0 sphine.-28 g.of 2,6,6-trimethylcyclohexanone-(1) were added to a solution of lithiumacetylide (prepared from 1.5 g. lithium in 700 ml. of liquid ammonia)and the mixture was stirred for 12 hours. Then 10 g. of ammoniumchloride were added, the ammonia was driven off and the residue taken upin diethyl ether. From this solution the solvent was driven off and theresidue was distilled in vacuo, whereby 32 g. of2,6,6-trimethyl-l-ethinylcyclohexanol (B. P 82-83"; n =l.4774) wereobtained. The latter was dissolved in 150 ml. of petroleum ether andhydrogenated at atmospheric pressure in the presence of 0.3 ml. ofquinoline and 3 g. of palladium lead catalyst (Lindlar, Helv. Chim. Acta35 [1952], 450). Upon 1 mol of hydrogen was taken up, the catalyst wasseparated by filtration, the solvent was driven off and the crude2,6,6-trimethyl-l-vinyl-cyclohexanol was dissolved in ml. of benzene andtreated at 50-60 with a little more than the calculated quantity ofphosphorus tribromide. After the reaction was completed the ben zenesolution was separated from the phosphorous acid formed, washed withcold sodium bicarbonate solution and water, dried over sodium sulfateand mixed with a solution of the equimolar quantity of triphenylphosphine in a little benzene. The reaction mixture was allowed to standfor 15 hours. Then the crystalline 2,6,6-trimethylcyclohex'yliden ethyltriphenylphosphonium bromide was collected and dried in vacuo (M. P.2l7-2l8). To 12.2 g. of2.6,6-trimethylcyclohexyliden-ethyl-triphenylphosphonium bromidesuspended in 125 ml. of dry diethyl ether was added in a nitrogenatmosphere a solution of 2.1 g. pbenyl lithium in ether. The phosphoniumbromide solubilised in an exothermic reaction and there was obtained adeep red solution of2,6,6-trimethylcyclohexyliden-ethyliden-triphenylphosphine which couldbe used without further purification for the process of Example 1.

EXAMPLE 2 (a) 4-[2,6,6-trimethylcyclohexylidenl-2-metlzyl-butenc-(2)-aZ'(1)-rlicthyl-acetal 3 g. of l,l-diethoxypropanone-(2) werecondensed with 2,6,6-trimethylcyclohexyliden ethylidentriphenylphosphine as described in Example 1 above. There was thusobtained4-[2,6,6-trimethylcyclohexyliden]-2-methylbuten-(2)-al-(l)-diethyl-acetalshowing an absorption maximum in the ultraviolet spectrum at 248 me inpetroleum ether.

(b) 4- [2,6,6-trimethyIcyclohexyIiden] -2-melhyl-butene- (D 5 g. of4-[2,6,6-trimethylcyclohexylidenl-2-methylbutene(2)-al-(l)-diethyl-acetal dissolved in 90 ml. of glacialacetic acid were mixed with 10 ml. of water and 10 g. of sodium acetateand the mixture was heated for 2 hours at 200 ml. of water were thenadded, and the mixture was extracted with petroleum ether; the petroleum ether solution was washed with water and 5% sodium bicarbonatesolution, dried over sodium sulfate and the solvent was driven oil.After distillation in vacuo there was obtained4-[2,6,6-trimethylcyclohexylidenl-2- methyl-butene-(2)-al-(l) of B. P.85; U. V. absorption maximum at 288 mg in petroleum other.

We claim:

l. A process for the manufacture of polycne aldehydes, which comprisescondensing in an inert solvent a compound selected from the groupconsisting of 2,6,6-trimethylcyclohexyliden ethyiiden triarylphosphine,2,6,6 trimethylcyclohexyiiden-ethyliden-tri alkyl-substituted aryl)phosphine and 2,6,6-trimethylcyclohexyliden-ethylidentri(alkoxy-substituted aryl) phosphine with a compound selected from thegroup consisting of acctals of 2-0xopropanal-(l), of4-oxopentene-(2)-al-(l) and of Z-methyl--oitO-heptadiene-(ZA)-al-(1),heating the reaction mixture and hydrolyzing the acetal formed in thepresence 3. A process according to claim 2 wherein 2-oxo-proof acid.panal-(1)-ethylene-acetal is employed.

2. A process for the manufacture of a polyene alde- 4. A processaccording to claim 2 wherein 2-oxo-prohyde which comprises condensing inan inert solvent pana1-(1)-dialkyl-acetal is employed. 2,6,6trimethylcyclohexyliden ethyliden triphenylphos- 5 phine and a2-0X0-propanal--(1)-acetal, heating the reac- N0 l'effirellcescitfidtion mixture and hydrolyzing the acetal formed in the presence ofacid.

1. A PROCESS FOR THE MANUFACTURING OF POLYENE ALDEHYDES, WHICH COMPRISESCONDENSING IN AN INERT SOLVENT A COMPOUND SELECTED FROM THE GROUPCONSISTING OF 2,6,6-TRIMETH YLCYCLOHEXYLIDEN - ETHYLIDENTRIARYLPHOSPHINE,2,6,6-TRIMETHYLCYCLOHEXYLIDEN-ETHYLIDEN-TRI(ALKYL-SUBSTITUTED ARYL)PHOSPHINE AND2,6,6-TRIMETHYLCYCLOHEXYLIDEN-ETHYLIDENTRI(ALKOXY-SUBSTITUTED ARYL)PHOSPHINE WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ACETALSOF 2-OXOPROPANAL-(1), OF 4-OXOPENTENE-(2)-AL-(1) AND OF2-METHYL-3-OXO-HEPTADIENE-(2,4)-AL-(1), HEATING THE REACTION MIXTURE ANDHYDROLYZING THE ACETAL FORMED IN THE PRESENCE OF ACID.